Method of producing herbicide intermediates

ABSTRACT

A method of producing alkyl 3-hydroxy-4-(4-hydroxyphenoxy)pentanoate which comprises the steps of: (a) reacting 4-benzyloxyphenol with an alkali hydroxide and 2-chloropropionic acid in the presence of a suitable solvent and at a temperature sufficient to cause formation of 2-(4-benzyloxyphenoxy)propionic acid; (b) reacting said 2-(4-benzyloxyphenoxy)propionic acid with a compound selected from phosgene, oxalyl chloride, thionyl chloride, or phosphorus trichloride, in the presence of a suitable catalyst and solvent and at a temperature sufficient to cause formation of 2-(4-benzyloxyphenoxy)propionyl chloride; (c) reacting said 2-(4-benzyloxyphenoxy)propionyl chloride with 2,2-dimethyl-1,3-dioxan-4,6-dione and pyridine, all in the presence of a suitable solvent and at a temperature sufficient to cause formation of 5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione; (d) reacting said 5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione with an alkyl alcohol for a period of time and at a temperature sufficient to cause formation of alkyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate; (e) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate with sodium borohydride in the presence of a suitable solvent and at a temperature sufficient to cause formation of alkyl 4-(4-benzyloxyphenoxy)-3-hydroxy-pentanoate; and (f) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-hydroxypentanoate with hydrogen in the presence of a suitable solvent, a suitable catalyst, and at a sufficient temperature to form the desired product, alkyl 3-hydroxy-4-(4-hydroxyphenoxy)pentanoate.

BACKGROUND OF THE INVENTION

The present invention relates to a method of producing alkyl3-hydroxy-4-(4-hydroxyphenoxy)pentanoates, compounds used as criticalintermediates in the production of aryloxy phenoxy pentanoateherbicides.

Aryloxy phenoxy alkyl acids and esters are well known herbicides andhave been found to be particularly useful as post-emergent herbicideswhen used against grassy-type weed pests. These aryloxy phenoxyherbicides can be made a number of different ways, however, the primarymethod described in the literature comprises initially reacting apyridine-type compound with a hydroguinone, followed by completion ofsubsequent processing steps. This method is described in U.S. Pat. Nos.4,152,328 and 4,216,007. A problem with this method is that the initialstarting compound, the pyridine-type compound, is very expensive, andsubsequent processing steps dilute the percentage of pyridine moietyending up in the end product, thus increasing significantly the cost ofthe final product which is obtained.

Desirably, the pyridine moeity is added at the end of the process inorder to maximize the percent yield, and minimize the expense of thepyridine-type compound.

The present invention is thus concerned with a method of producingintermediates for the aryloxy phenoxy-type herbicides whichintermediates enable the pyridyl moiety to be added at the end of theentire process. Such intermediates are alkyl3-hydroxy-4-(4-hydroxyphenoxy)pentanoates.

DESCRIPTION OF THE INVENTION

A method of producing alkyl 3-hydroxy-4-(4-hydroxyphenoxy)pentanoatewhich comprises the steps of:

(a) reacting 4-benzyloxyphenol with an alkali hydroxide and2-chloropropionic acid in the presence of a suitable solvent and at atemperature sufficient to cause formation of2-(4-benzyloxyphenoxy)-propionic acid;

(b) reacting said 2-(4-benzyloxyphenoxy) propionic acid with phosgene,oxalyl chloride, thionyl chloride or phosphorus trichloride, in thepresence of a suitable catalyst and solvent and at a temperaturesufficient to cause formation of 2-(4-benzyloxyphenoxy)propionylchloride;

(c) reacting said 2-(4-benzyloxyphenoxy)propionyl chloride with2,2-dimethyl-1,3-dioxan-4,6-dione and pyridine, all in the presence of asuitable solvent and at a temperature sufficient to cause formation of5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione;

(d) reacting said5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dionewith an alkyl alcohol for a period of time and at a temperaturesufficient to cause formation of alkyl4-(4-benzyloxy-phenoxy)-3-oxopentanoate;

(e) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate withsodium borohydride in the presence of a suitable solvent and at atemperature sufficient to cause formation of alkyl4-(4-benzyloxyphenoxy)-3-hydroxypentanoate; and

(f) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-hydroxypentanoate withhydrogen in the presence of a suitable solvent, a suitable catalyst, andat a sufficient temperature to form the desired product, alkyl3-hydroxy-4-(4-hydroxyphenoxy)pentanoate.

Alternatively, steps (e) and (f) may be reversed and step (e) may bereplaced by a catalytic hydrogenation, possibly in combination with step(f).

This process can be represented schematically as set forth below, apreferred process being indicated. ##STR1## wherein R is an alkyl grouphaving from about 1 to 18 carbon atoms.

Potassium hydroxide is the preferred alkali hydroxide for use in step(a) of the invention; however, sodium hydroxide would also be suitable.In addition, toluene is the preferred solvent, but other organicsolvents of the same or similar type would be acceptable.

The temperature of the first step of the reaction in accordance with thepreferred embodiment is normally carried out between about 20° to about150° C., with 85° C. being preferred.

In step (b) of the reaction of the invention, the preferred compound forreacting with 2-(4-benzyloxyphenoxy)propionic acid is phosgene. However,other phosgene substitutes can be used, such as oxalyl chloride, thionylchloride or phosphorus trichloride. In addition, the preferred catalystis dimethylformamide, but other catalysts, such as imidazole, tertiaryamines and amides could be used. Again, toluene is the preferred solventand the reaction is normally carried out between about 0° C. and 140°C., with 70° being preferred.

In step (c) of the process of the invention, methylene dichloride ispreferred for use as the solvent. Other suitable solvents would includehydrocarbons and halocarbons such as toluene and chloroform.

The reaction is conventionally carried out at between -40° C. and 80° C.2,2-Dimethyl-1,3-dioxan-4,6-dione, one of the reactants in step (c) ofthe process, is commonly known as Meldrum's acid.

In step (d) of the process of the invention, ethyl alcohol is thepreferred reactant to combine with the Meldrum's acid adduct,5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione;however other alkanols such as methanol, isopropanol, etc. could beused. When ethanol is the alcohol of choice, the reaction is normallycarried out at a temperature range between about 20° C. and about 150°C., with 60° C. being preferred.

Any alcohol having a carbon chain ranging from about 1 to about 20carbon atoms can be used.

In step (e) of the process the reaction is normally carried out in thepresence of ethyl alcohol; however other solvents such as methanol,isopropanol, etc., corresponding to the alkanol of step (d) could beused. The reaction is normally carried out at temperatures ranging from-40° to about 80° C.

In the next step of the reaction (step f), the hydrogenation step, thepreferred catalyst is a palladium/carbon catalyst and the reaction iscarried out in the same solvent as step (e) and hydrochloric acid at atemperature ranging from about 0° to about 150° C.

This invention will be more clearly understood by reference to thefollowing examples, which are intended to be illustrative of theprocess, but not limiting thereof.

EXAMPLE I Preparation of Benzyloxyphenoxypropionic Acid

A three-liter, four-necked, round-bottom flask was obtained and fittedwith a thermocouple and temperature controller, a heating mantle, andaddition funnel, a nitrogen line connected to a nitrogen/vacuum source,a condenser, an overhead stirrer, and a catch basin. Into this flask wascharged 420 grams (g) (2.1 moles) of benzyloxyphenol, 216.2 g (5.4moles) sodium hydroxide, and 700 milliliters (ml) toluene. Additionally,250 ml (2.9 moles) of chloropropionic acid was charged into the funneland nitrogen was added to replace the atmosphere in the flask. Thecontents were then heated to 95° C. with stirring. The reaction wasconducted over a period of several hours, and during that timequantities of chloropropionic acid were added to prevent solidificationof the reaction materials. During the same period of time an additionalquantity of sodium hydroxide was added to facilitate the reaction.

At the end of the first day, the stirring was stopped, and the flaskleft under a nitrogen atmosphere overnight. The next day, the flask washeated to 95° C. and more chloropropionic acid (60 ml) was added. Afterabout 4 additional hours of addition of chloropropionic acid thereaction was stopped and the subject propionic acid product wasisolated.

EXAMPLE II Preparation of Benzyloxyphenoxypropionyl Chloride

A three-liter, round-bottom flask was obtained and fitted with anoverhead stirrer, a thermocouple, a temperature controller, an additionfunnel with a cold trap overhead, and a line leading to a phosgenecyclinder. Also it was fitted with an exit line to a nitrogen/vacuumsource, a heating mantle, and a catch basin. The exit line went to acondenser and a caustic scrubber. Into this flask was placed 183.2 g(0.67 mole) benzyloxyphenoxypropionic acid, 900 ml of toluene, and 2.9 g(0.04 mole) dimethylformamide. The phosgene cyclinder was turned on and75 ml (1.05 moles) phosgene was allowed to accumulate in the funnel. Thereactants were heated to 80° C. with stirring while the phosgene wasadded thereto. During the course of the phosgene addition, solids formedin the flask; however, ultimately they went into solution. After thephosgene addition, nitrogen was slowly added to the flask. The reactionwas stopped, and a vacuum pulled on the flask to boil off the excessphosgene. The flask was then placed under a nitrogen atmosphere. Thesolvent was stripped off, leaving 233.2 g of yellow solids, which wereidentified by suitable analytical techniques as being the subjectcompound.

EXAMPLE III Preparation of5-[2-(4-Benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione

A three-liter, four neck flask equipped with a thermometer, overheadstirrer, addition funnel, and a line to a nitrogen/vacuum source wasobtained and placed in a dry ice/isopropanol bath. To the flask wascharged 281.0 ml (1.95 moles) of Meldrum's acid, 600 ml of methylenedichloride, and 290 ml (3.6 moles) pyridine. The contents were thencooled to -10° C. and placed under the nitrogen atmosphere.Benzyloxyphenoxypropionyl chloride (596.5 g, 1.71 mole) was dissolved in300 ml methylene dichloride, and placed in an addition funnel. Thecontents of the addition funnel were then added to the round-bottomflask over a period of time. Approximately two hours after the additionwas complete, 307 ml concentrated hydrochloric acid in ice and enoughice water to fill the flask were added. The contents were then pouredinto a separation funnel, the flask rinsed, and 100 ml of a 1:1methylene dichloride:ice water aqueous solution was added to the funnel.The material then solidified, and to this was added one liter methylenedichloride which caused a separation of the contents into an organicphase and an aqueous phase. The organic phase contained a quantity ofsolids. The aqueous phase was removed and the organic phase and solidswere stirred with 600 ml ice water and enough methylene dichloride todissolve the solids (approximately 600 ml). The phases were thenseparated, and the organic phase dried over sodium sulfate, and strippedon a rotary evaporator. When the organic phase was mostly stripped, butstill containing a considerable amount of solvent, 600 ml anhydrousethanol was added to prevent the product from crystallizing in anunworkable form and the reaction vessel placed in a refrigerator. Thecontents were later analyzed by suitable analytical techniques and foundto be the subject compound dissolved in solvent.

EXAMPLE IV Synthesis of Ethyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate

A three-liter, four-necked, round-bottom flask equipped with a heatingmantle, a catch basin, a condenser, thermometer, overhead stirrer, and aline to a nitrogen/vacuum source was obtained, and into this flask wasplaced 681 g (1.71 mole) of the Meldrum's acid adduct prepared inaccordance with Example III above, along with a quantity of ethanol, andthe reactants were then heated and stirred under a nitrogen atmosphere.As the contents were heated, some refluxing and off-gassing occurred,and most of the solids dissolved, with concomitant off-gassing. Afterapproximately 3 hours, the heating was stopped and the stirring stopped.The reaction mixture was then stripped on a rotary evaporator at 50° C.,and there was obtained 605.7 g of an oil, identified by analyticaltechniques as being the subject compound.

EXAMPLE V Synthesis of Ethyl 4-(4-benzyloxyphenoxy)-3-hydroxypentanoate

A three-liter, four-necked flask fitted with an overhead stirrer,thermometer, a line to a nitrogen/vacuum source via a Firestone valve,and a water/ice bath underneath was obtained. To this flask was charged580.1 g (1.70 mole) of the beta-ketoester formed in accordance withExample IV above, 1000 ml of ethanol, and 22.1 g (0.58 mole) of sodiumborohydride, which was added portion wise over a period of time,checking the extent of the reaction after each addition. Thereafter 800ml each of water and methylene dichloride were added, and the phasesseparated. The organic phase was washed with 600 ml of water and 150 mlsaturated ammonium chloride solution. The phases were again separated.The organic phase was dried over sodium sulfate, stripped with a rotaryevaporator at approximately 50° C. There was obtained 520.5 g of an oil.The HPLC showed the product to be the subject compound.

EXAMPLE VI Synthesis of Ethyl 3-hydroxy-(4-hydroxyphenoxy)pentanoate

A three-liter, four-neck flask with a round bottom, equipped with amechanical stirring device, a thermometer, a gas inlet, and a Firestonevalve, was obtained and into this flask was charged 499.5 g (1.46 mole)of the beta-hydroxy ester compound formed in accordance with Example Vabove, and 1600 ml of ethanol and then placed under a nitrogenatmosphere. Eleven grams of a palladium on carbon catalyst was thenadded and the atmosphere exchanged several times for nitrogen. TheFirestone valve was then closed and the line removed from the nitrogenand placed on a hydrogen cylinder and the hydrogen flow was adjustedwith the Firestone valve closed. The flask was evacuated and theatmosphere exchanged two times with hydrogen and the hydrogen flow wasthen adjusted to the slowest bubbling rate from the Firestone valve.After several hours had elapsed, the mixture was filtered and strippedwith a rotary evaporator and there was obtained 408.9 g of a dark oilwhich was identified as being the subject compound, namely, ethyl3-hydroxy-4-(4-hydroxyphenoxy)pentanoate.

It will be recognized by those skilled in the art that variations inmolar ratios, times, temperatures, and solvents used in the varioussteps in the process of the invention can be made without departing fromthe spirit and scope of the claims as appended.

What is claimed is:
 1. A process of producing alkyl 3-hydroxy-4-(4-hydroxyphenoxy)-pentanoate which comprises the steps of:(a) reacting 4-benzyloxyphenol with an alkali hydroxide and 2-chloropropionic acid in the presence of a suitable solvent and at a temperature sufficient to cause formation of 2-(4-benzyloxyphenoxy)-propionic acid; (b) reacting said 2-(4-benzyloxyphenoxy)propionic acid with a compound selected from phosgene, oxalyl chloride, thionyl chloride, or phosphorus trichloride, in the presence of a suitable catalyst and solvent and at a temperature sufficient to cause formation of 2-(4-benzyloxyphenoxy)propionyl chloride; (c) reacting said 2-(4-benzyloxyphenoxy)propionyl chloride with 2,2-dimethyl-1,3-dioxan-4,6-dione and pyridine, all in the presence of a suitable solvent and at a temperature sufficient to cause formation of 5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione; (d) reacting said 5-[2-(4-benzyloxyphenoxy)propionyl]-2,2-dimethyl-1,3-dioxan-4,6-dione with an alkyl alcohol for a period of time and at a temperature sufficient to cause formation of alkyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate; (e) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate with sodium borohydride in the presence of a suitable solvent and at a temperature sufficient to cause formation of alkyl-4-[4-benzylphenoxy)-3-hydroxy-pentanoate; and (f) reacting said alkyl 4-(4-benzyloxyphenoxy)-3-hydroxypentanoate with hydrogen in the presence of a suitable solvent, a suitable catalyst, and at a sufficient temperature to form the desired product, alkyl 3-hydroxy-4-(4-hydroxyphenoxy)pentanoate.
 2. The process of claim 1 wherein the alkali hydroxide in step (a) is potassium hydroxide.
 3. The process of claim 1 wherein phosgene is used as the reactant in step (b).
 4. The process of claim 1 wherein dimethylformamide is used as the catalyst in step (b).
 5. The process of claim 1 wherein methylene dichloride is used as the solvent medium in step (c).
 6. The process of claim 1 wherein palladium on carbon is used a the catalyst in step (f).
 7. The process of claim 1 wherein step (e) consists of reacting said alkyl 4-(benzyloxyphenoxy)-3-oxopentanoate with hydrogen in the presence of a suitable catalyst and solvent at a temperature and pressure sufficient to cause formation of alkyl 3-hydroxy-4-(benzyloxyphenoxy)-pentanoate.
 8. The process of claim 7 wherein the catalyst is platinum dioxide.
 9. The process of claim 7 wherein steps (e) and (f) are combined into a single step. 